Table 2.
In silico variant analysis.
| Patient ID | Status | Genomic Position | DNA Variant | Protein Variant | Variant Type | GnomAD AF (NFE) |
In Silico Prediction | ACMG Rules | ACMG Classification |
Reference | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| IA-CIC08269 | Homozygous | 76232616 | c.1920G>A | p.(Trp640*) | Nonsense | 0 | CADD | 36.0 | PVS1 Very strong | Pathogenic | This study |
| PM2 Moderate | |||||||||||
| PP3 Supporting | |||||||||||
| PP4 Supporting | |||||||||||
| PP5 Supporting | |||||||||||
| XZ-358338 | Compound Heterozygous | 76147917 | c.211C>T | p.(Arg71*) | Nonsense | 0.00002 | CADD | 35.0 | PVS1 Very strong | Pathogenic | Zampaglione 2020 |
| PM2 Moderate | |||||||||||
| PM3 Moderate | |||||||||||
| PP3 Supporting | |||||||||||
| PP4 Supporting | |||||||||||
| PP5 Supporting | |||||||||||
| 76167836_ 76292188 | c.585+2223_3326+5684del | p.(Pro196Glufs*47) | Exons 8-28 deletion | 0 | PVS1 Very strong | Pathogenic | This study | ||||
| PM2 Moderate | |||||||||||
| PM3 Moderate | |||||||||||
| PP3 Supporting | |||||||||||
| PP4 Supporting | |||||||||||
| PP5 Supporting | |||||||||||
| IM-4476 | Compound Heterozygous | 76213058_ 76365878 | c.1487+1134_3741- 2607delins15 |
p.(Ser497_Lys1247del) | Exons 18-30 deletion | 0 | PVS1 Very strong | Pathogenic | This study | ||
| PM2 Moderate | |||||||||||
| PP3 Supporting | |||||||||||
| PP4 Supporting | |||||||||||
| PP5 Supporting | |||||||||||
| 76231034 | c.1627G>A | p.(Glu543Lys) | Missense | 0.0003 | Conservation (Grantham) | 56 (0–215) | PS3 Strong | Pathogenic | Sergouniotis 2014 | ||
| CADD | 27.6 | PM2 Moderate | |||||||||
| SIFT | Deleterious (score: 0.02) |
PP3 Supporting | |||||||||
| Polyphen2 | Probably Damaging (1.000) | PP4 Supporting | |||||||||
| PP5 Supporting | |||||||||||
| HD-2011304 | Compound Heterozygous | 76211911 | c.1474T>A | p.(Trp492Arg) | Missense | 0 | Conservation (Grantham) | 101 (0–215) | PM2 Moderate | Likely Pathogenic * | This study |
| CADD | 28.3 | PM3 Moderate | |||||||||
| SIFT | Deleterious (score: 0) |
PP3 Supporting | |||||||||
| Polyphen2 | Probably Damaging (0.995) | PP4 Supporting | |||||||||
| 76231034 | c.1627G>A | p.(Glu543Lys) | Missense | 0.0003 | Conservation (Grantham) | 56 (0–215) | PS3 Strong | Pathogenic | Sergouniotis 2014 | ||
| CADD | 27.6 | PM2 Moderate | |||||||||
| SIFT | Deleterious (score: 0.02) |
PP3 Supporting | |||||||||
| Polyphen2 | Probably Damaging (1.000) | PP4 Supporting | |||||||||
| PP5 Supporting | |||||||||||
| EB-163150 | Compound Heterozygous | 76211436 | c.1282-2A>G | p.(?) | Splicing | 0.000009 | CADD | 34.0 | PVS1 Very strong | Pathogenic | This study |
| SpliceSiteFinder | −100% | PM2 Moderate | |||||||||
| MaxEnt | −100% | PP3 Supporting | |||||||||
| SpliceAI | 0.85 | PP4 Supporting | |||||||||
| 76219261 | c.1513A>G | p.(Met505Val) | Missense | 0.00005 | Conservation (Grantham) | 21 (0–215) | PM2 Moderate | Likely Pathogenic * | This study | ||
| CADD | 23.0 | PM3 Moderate | |||||||||
| SIFT | Tolerated (score: 0.2) |
PP3 Supporting | |||||||||
| Polyphen2 | Possibly Damaging (0.786) | PP4 Supporting | |||||||||
* Stand Alone VUS becoming Likely Pathogenic with a pathogenic variant in trans.